Current treatment options for patients with lower extremity peripheral artery disease (PAD) are limited with appropriately heavy emphasis placed on cardiovascular risk factor modification to prevent coronary or cerebrovascular events in these high-risk patients. Unfortunately, with regard to limb-related outcomes, to date, no pharmacologic therapy has convincingly been shown to prevent clinically overt disease in asymptomatic individuals and among symptomatic patients, too few medical options exist to ameliorate claudication, improve physical function, or prevent local progression to limb threatening disease. This ancillary study proposal will extend the inflammatory hypothesis of atherothrombosis currently being tested in the Cardiovascular Inflammation Reduction Trial (CIRT) to encompass lower extremity peripheral atherosclerosis, a disease which frequently co-exists with coronary disease and shares many antecedent risk factors including type 2 diabetes (T2D), metabolic syndrome (MetS) and subclinical inflammation. CIRT is an NHLBI funded multicenter clinical trial (U01 HL101422 and U01 HL101389) that will randomly allocate 7,000 subjects with prior myocardial infarction (MI) and either T2D and/or MetS to low dose methotrexate (LDM; target dose 15 to 20 mg per week) plus usual care or placebo plus usual care over a follow-up period of 2 to 4 years (average 3 years). Participants will be recruited from roughly 350 to 400 clinical sites in the United States and Canada. The primary endpoint is nonfatal MI, stroke, and cardiovascular death. While PAD is a tertiary endpoint of the trial, endpoint adjudication and ankle-brachial index (ABI) measurement for diagnosis and monitoring of disease are currently not funded by the trial. We propose to evaluate in a randomized, double-blind, placebo-controlled setting whether LDM will 1) reduce PAD progression as assessed by change in ABI, 2) retard functional decline as measured by change in both questionnaire-based and performance- based physical function measures and correlated with change in ABI, and 3) reduce the occurrence of PAD events including confirmed intermittent claudication, critical limb ischemia, lower extremity revascularization, amputation, or new occurrence of ABI < 0.9. In summary, we believe that the research infrastructure of the parent CIRT trial offers a unique and extremely cost-effective opportunity to answer important and timely questions about the potential benefits of anti-inflammatory therapy for the prevention and treatment of lower extremity PAD. We seek funds to support endpoint validation and to provide CIRT recruiting sites with Doppler ABI equipment for ascertainment of the ABI thus effectively elevating PAD to an adjudicated endpoint of the trial and now incorporating a diagnostic modality widely acceptable to the PAD research community. In order to achieve a sufficiently large sample size to address our scientific goals, this natural extension of the parent study must be undertaken in parallel with overall CIRT recruitment which began in April 2013.